DESCRIPTION: (As provided by Applicant) This NRSA application targets one of the most important clinical issues in neurofibromatosis (NFl). Astrocytomas are the second most common tumor in NF1, often leading to blindness and neurologic impairment. Our ability to design rational therapies for these tumors is heavily dependent on a more complete understanding of the role of the Nfl gene in the development of astrocytomas. In this grant, we propose to critically test the hypothesis that loss of neurofibromin expression results in astrocytoma formation. Specifically, we plan to (1) determine the effect of loss of neurofibromin expression in vivo using a conditional knockout mouse in which Nfl gene expression has been disrupted in astrocytes by using the Cre/Lox P recombination system and (2) determine the effect of loss of neurofibromin expression in vitro by inactivating the Nfl gene in primary astrocyte cultures. Astrocytes in culture will be assessed for their growth and tumorigenic properties and since neurofibromin is a negative regulator of p21-ras, downstream effectors of the p21-ras signaling pathway will be measured.